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New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures...

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Page 1: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Mechanisms, Testing and Treatment of Neonatal Seizures

Christopher Smyser, M.D. 20th International Symposium on Neonatology

September 10th, 2015

Page 2: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Clinical Case

• 38 week male infant born to 27 y.o. mother

• Pregnancy uncomplicated

• NSVD

• Apgars 9 and 9 at 1 and 5 minutes

• Taken to Newborn Nursery

• Nursing without difficulty

• Discharge planning commenced

Page 3: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Clinical Case

• ~36 hours of life witnessed to have right-sided tonic-clonic movements with associated circumoral cyanosis

• Multiple episodes lasting 20 secs to 2 mins

• Loaded with 20 mg/kg phenobarbital

• Antibiotics started

• Encephalopathic on examination

Page 4: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Questions

• Is the infant having seizures?

• How do we best determine this?

• How do we manage this patient?

• What testing needs to be performed (if any)?

• How do we counsel the family?

Page 5: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Epidemiology

• Most frequent neurological event in newborns

• Most common time for acute seizures

• 1-5/1000 term births

• 10-15/1000 preterm births

• As many as 64/1000 very preterm births

• 1/3 first day of life, another 1/3 first week of life

• Maternal, intrapartum, infant risk factors

Kirmse 2011, Uria-Avellanal 2013, Vasudevan 2013, Glass 2015, Pisani 2015

Page 6: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

1. Etiology

2. Diagnosis

3. Evaluation

4. Management

5. Outcomes

Neonatal Seizures – Overview

Page 7: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

1. Etiology

Page 8: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Glass 2014

Etiology

Page 9: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

HIE

ICH

Stroke

Malformations

Meningitis

Metabolic

Other

Etiology

Vasudevan 2013

Page 10: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Excitatory Factors

• Glutamate receptor overexpression

– Major excitatory neurotransmitter in CNS

– Subtypes NMDA, AMPA, kainate

– Prevalent in hippocampus and cortex

Jensen 2009

Page 11: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Inhibitory Factors

• GABA – excitatory in infants – Allow Cl- influx into cells, results in hyperpolarization

– Principal inhibitory neurotransmitter in adults

Jensen 2009, Kirmse 2013

Page 12: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

E:I Balance

• Excitatory:Inhibitory ratio differs in infants

Excitation

Inhibition

• Higher membrane resistance • Altered structure of NMDA/AMPA • GABA depolarizing

Goldberg 2011, Kirmse 2013

Page 13: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Biochemical Effects

• Increase in energy consumption

– ↓ ATP, ↑ ADP

– ↑ pyruvate production → ↑ lactate production

– ↑ lactate → vasodilatation and ↑ CBF

• Seizures in animal models result in depletion of cerebral glucose within 5 minutes

– Undetectable by 30 minutes

Wasterlain 2013

Page 14: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

CBF and Brain Metabolism

Wasterlain 2013

Page 15: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Impact of Seizures on the Brain

Miller 2002

↑15%

↑21%

Page 16: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Mechanisms of Injury

• ↑ CBF may cause hemorrhage/reperfusion injury

• Potential for metabolic demand to outweigh substrate delivery – Neuronal loss

– Injured brain more vulnerable, exacerbates injury

– Less likely in infants than adults

• Excitatory amino acids – Glutamate (↑ production and ↓ uptake)

– Limbic system particularly susceptible

Chapman 2012

Page 17: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

2. Diagnosis

Page 18: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Semiology

• Clinical assessment ~50% accurate

• Mixed semiology – ocular movements, tongue thrusting, cycling, apnea, vital sign changes

• Generalized seizures rare

• Mimics state and age dependent – tremor, myoclonus, hyperekplexia, opsoclonus, tonic gaze, Sandifer syndrome, hiccups, fasciculations…

Glass 2014, Orivoli 2015

Page 19: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

The Problem

EEG only

Seizures Clinical

Seizures

E-C

Seizures

Page 20: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

• 30-90% of seizures are subclinical

• 66% of abnormal movements suspected to be seizures have NO EEG correlate

• Clinical seizures often subtle

• Electromechanical dissociation in 50-60% following anticonvulsant therapy

• Similar in term and preterm infants

• Background equally important

EEG Monitoring

Mizrahi and Kellaway 1987, Connell 1989, Boylan 2002, Scher 2003, Murray 2007, Lawrence 2009, Uria-Avellanal 2013, van Rooij 2013, Chang and Tsuchida 2014

Page 21: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

• Requires at least 11 electrodes and EKG lead

• Record 60 minutes for routine study

• Synchronized video

recordings

• Bedside annotation

and education

EEG Monitoring

Chang and Tsuchida 2014, Shellhaas 2015

Page 22: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

EEG Monitoring

Page 23: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

EEG Monitoring

Shah 2014

Page 24: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

EEG Monitoring

Glass 2014

Page 25: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

EEG Monitoring Importance

• 51 infants with encephalopathy or HIE risk

– 12 infants with seizures and/or treated with AEDs

– 48/526 EEG seizures (9%) clinically recognized

– 77% of clinical events with no EEG correlate

– 3 infants “aggressively treated” for up to 31 clinical events with NO EEG seizures

– 2 infants did not receive any anticonvulsant therapy and had 38 and 56 EEG seizures

– 5/12 infants (42%) received incorrect therapy

Murray 2007

Page 26: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

• 400 high-risk infants underwent VEEG

– Monitored 22-87 hours

– 26% of monitored infants with seizures

– 24% of seizures with no EEG correlate

– 13% concerning clinical events with no EEG change

– VEEG results changed management in 1/3 of cases

Wietstock 2015

EEG Monitoring Importance

Page 27: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

EEG Practical Considerations

• Feasibility – Who? When? With what? How long?

– What are you going to do with the information?

– Is it going to change your management?

• Equipoise regarding treatment of isolated, short electrographic seizures

• Consensus exists regarding treatment of status epilepticus

Page 28: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Who to Monitor

Chang and Tsuchida 2014

Page 29: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

ACNS Guidelines

• Clinical scenarios to consider EEG monitoring:

– Acute neonatal encephalopathy or stroke

– Severe cardiac/pulmonary disease (ECMO/PHTN)

– CNS infection

• GBS sepsis, meningoencephalitis

– CNS trauma

• Bleeding

– Inborn error of metabolism

– Cerebral dysgenesis

Shellhaas 2011

Page 30: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

ACNS Guidelines

• EEG monitoring recommended for:

– Evaluation of evolution of background

– Monitor for seizures

• Importance of synchronized video

• Importance of bedside observer to annotate

• Recommend 24 hours of monitoring in “high-risk” neonates to look for seizure onset

• Continue monitoring for 24 hours after last seizure

Shellhaas 2011

Page 31: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Post-Operative Setting

• Seizures common in post-operative setting

• 8% infants with CHD with seizures post-op

• 85% electrographic only

• 62% with status

• Delayed closure and

prolonged circulatory

arrest associated with

increased seizures

Naim 2015

Page 32: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

3. Evaluation

Page 33: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Diagnostic Testing

• Serum Studies:

– Every patient: Glucose, lytes, iCa, Mg, Phos, CBC

– Consider: lactate/pyruvate, amino acids, ammonia, CK, carnitine, acylcarnitine, biotinidase, uric acid, cholesterol, fatty acids, pipecolic acid, copper/ceruloplasmin

• Urine:

– Consider: organic acids, sulfites, uric acid, acylglycines, xanthine, guanidoinoacetate, pipecolic acid

Page 34: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Diagnostic Testing

• Lumbar Puncture:

– Every patient: Routine studies including culture (REMINDER: obtain concurrent serum glucose)

– Consider: HSV PCR based upon course

– Consider: lactate/pyruvate, amino acids (elevated CSF glycine), neurotransmitter metabolites (prior to pyridoxine)

• EEG:

– Every patient: Obtain routine EEG

– Determine need for treatment and/or VEEG monitoring

Page 35: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Hearing Protection for Scanning

Page 36: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Vacuum Fix Papoose

Page 37: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Vacuum Fix Papoose

Page 38: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

RF Coil

Page 39: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

MRI

Page 40: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

MRI

Page 41: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

MRI

Page 42: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

MRI

Page 43: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

MRI

Page 44: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

4. Management

Page 45: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Acute Management

For acute seizures without correctable etiology:

1. Bolus with IV phenobarbital 20 mg/kg

2. 2nd bolus with IV phenobarbital 20 mg/kg

3. Bolus with IV Fosphenytoin 20 mg/kg

4. Bolus with Versed 0.1 mg/kg and begin infusion at 0.1 mg/kg/hr. Adjust infusion in 0.1 mg/kg increments

5. Consider IV pyridoxine 100-200 mg followed by 100 mg every 10 minutes until total of 500 mg (or 30 mg/kg)

6. Consider LP for neurotransmitter metabolites followed by folinic acid 2.5 mg (or 4 mg/kg/dose) every 12 hours

Page 46: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Chronic Management

• Consider maintenance meds based upon course

• Frequently phenobarbital 4-5 mg/kg/d divided BID

• Alternatives:

–Topiramate 3-5 mg/kg/day to start; PO only

– Levetiracetam 40-60 mg/kg/day divided BID; IV and PO

–Bumetanide trials with 0.1-0.3 mg/kg

• Consider early discontinuation of maintenance meds – as early as 2-4 weeks after last seizure

Pressler and Mangum 2013, Glass 2014

Page 47: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Levetiracetam

• Mechanism of action incompletely understood

• Requires higher loading and maintenance doses

• Optimal dosing unknown

• Alters burst firing but not normal activity

• No apoptotic effects in animal models

• Ongoing studies for efficacy – 35-80%?

• Common off label use as second line agent

Pressler and Mangum 2013, Glass 2014, Mruk 2015

Page 48: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Bumetanide

• Loop diuretic with rapid onset, short half-life

• Reverses depolarizing action of GABA

• Possibly augments phenobarbital efficacy

• Concern for ototoxicity

• NEMO trial – no improvement in seizure control and possible increased risk for hearing loss

Pressler and Mangum 2013, Pressler 2015

Page 49: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Topiramate

• Reduces action potential frequency during depolarization

• Modulates GABA activity

• Weakly antagonizes kainate/glutamate and AMPA

• Neuroprotective in animal models of injury

• No IV formulation for neonates – coming soon?

• Concern for neurocognitive effects

Tulloch 2012, Pressler and Mangum 2013, Glass 2014

Page 50: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

• Administered as continuous infusion

• Potential as second or third line therapy

• Cannot use with fosphenytoin

• Requires continuous cardiac monitoring

• Response rate 70-92%

• Concern for cardiac side effects though multiple studies have demonstrated safety

Lidocaine

Tulloch 2012, Lundquist 2013, van Rooij 2013

Page 51: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

5. Outcome

Page 52: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Seizures and Outcome

• Seizures affect developing brain – new injury or worsening of existing injury?

• Main predictor of outcome underlying etiology

• Mortality 7-16% term infants, 22-58% preterm

• Morbidity as high as 50% in term infants: – 27% with epilepsy

– 25% with cerebral palsy

– 20% with mental retardation

– 27% learning disabilities

– Often affects multiple domains

Ronen 2007, Uria-Avellanal 2013, Mruk 2015

Page 53: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Effect of Seizure vs Injury

• 77 term infants at risk for HIE with MRI scans

• 32% with clinically identified seizure events

• After controlling for severity of injury on MRI

– Worse motor and cognitive outcomes at age 4 years in subjects with clinical seizures

– Magnitude of effect varied with seizure severity

Glass 2009

Page 54: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

EEG Seizures and Outcome

• 59 neonates with EEG documented seizures

– 5 died – 4 as neonates

– 44% survivors moderately impaired

– 13% survivors severely impaired

– Greater seizure severity assoc with worse outcomes

– No relationship between outcome and AED response

– Higher risk for poor outcome if developed epilepsy

Painter 2012

Page 55: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

• 16-25% risk of developing epilepsy

• Onset in first year of life up to 70% of cases

• Higher risk in subjects with status epilepticus and brain injury on MRI scan

• 80% with associated neurological impairment; most commonly CP or intellectual disability

Epilepsy Risk

Glass 2011, Pisani 2015

Page 56: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Status Epilepticus

• 47 infants with SE (19 preterm and 28 term)

• Mortality 52% preterm vs. 17.8% term

• Adverse outcome 100% preterm vs. 75% term

• Developmental delay 47%

• Cerebral palsy 40%

• Epilepsy 50%

Pavlidis 2015

Page 57: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Monitoring and Treatment Likely Improves Outcomes

Page 58: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Summary

Page 59: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Summary

• Neonatal seizures are common, under recognized

• Majority are subclinical

• EEG monitoring for first 24 hours

• Consensus on treatment of status epilepticus and frequent clinical/subclinical EEG seizures

• Prolonged seizures can result in impaired development and susceptibility to seizures later in life due to altered hippocampal circuitry

Page 60: New Mechanisms, Testing and Treatment of Neonatal Seizures · 2016. 6. 27. · •Neonatal seizures are common, under recognized •Majority are subclinical •EEG monitoring for

Summary

• Phenobarbital remains first line drug – despite 50% efficacy and developmental concerns

• Majority of AEDs have potential negative effects (except levitericetam and topiramate)

• Limited data on monotherapy for levitericetam

• Many neonates with symptomatic seizures do not need maintenance AEDs

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